The prior art is replete with attempts to deliver therapeutic agents to a specific cell. Chemotherapeutic agents, for example, preferentially exert their effects at tumor cites due to the prolific cell growth that occurs in cancerous tissues. It has been a long standing objective to control the delivery of biologically active compounds and/or exogenous genes (“gene therapy”) to a cell.
Virus-like particles, often derived from known viruses, have been adapted to carry therapeutic agents. Using such methodology a multitude of compounds have been introduced to cells, including genes, antigens, and toxins.
A lipid-entrapped, polycation-condensed DNA system has been previously disclosed in U.S. Pat. No. 6,436,708 to Leone et al., (“Delivery system for gene therapy to the brain”) that can exert its effect for up to ten months. This reference fails to teach or suggest a means for the selective release of genes in response to an external signal. The reference also fails to teach or suggest the release of mRNA and the synthesis of proteins within the encapsulation device. The content of U.S. Pat. No. 6,436,708 is hereby incorporated by reference into this specification.
U.S. Pat. Nos. 6,620,617; 6,475,779 and 6,262,034 to Mathiowitz et al, (“Polymeric gene delivery”) discloses a gene therapy method wherein the genes to be introduced are encapsulated within a biodegradable matrix. As the matrix is slow degraded, the gene is gradually released. U.S. Pat. Nos. 6,247,720 and 6,677,313 to Mathiowitz et al., (“Method for gene therapy using nucleic acid loaded polymeric microparticles”) discloses a method for orally administering gene therapy. The content of U.S. Pat. Nos. 6,620,617; 6,475,779; 6,262,034; 6,247,720; and 6,677,313 is hereby incorporated by reference into this specification.
U.S. Pat. Nos. 5,584,807 and 5,865,796 to McCabe (“Gas drive gene delivery instrument”) describes the delivery of genetic material through nebulized microparticles. A variety of techniques are described which enable one to coat microparticles with a variety of substrates including DNA, RNA, and “other types of biological materials such as peptides, cytokines, hormones, or protein.” McCabe also describes the effects of microparticles on an organism. “It has been found that carrier particles of a size of a few microns can enter living cells, by penetrating the cell walls thereof, without unduly adversely affecting the ability of most of the living cells to survive. In other words, the carrier particles can enter living cells without killing them, to thus deliver the biological material on the particles into the cell.” The content of U.S. Pat. Nos. 5,584,807 and 5,865,796 is hereby incorporated by reference into this specification.
A similar enzymatically degradable gelatin based system is taught in U.S. Pat. Nos. 6,410,517 and 6,410,517 to Truong et al., (“Targeted gene delivery system”). The gene delivery method utilizes recognition molecules to promote target specificity. “The linkage design allows the attachment of any molecule onto the microparticle surface including antibodies, cell adhesion molecules, hormones and other cell-specific ligands.” A similar disclosure may be found in U.S. Pat. No. 6,025,337 to Thuong et al, (“Solid microparticles for gene delivery”).
U.S. Pat. No. 6,420,176 to Lisziewicz et al, (“Compositing for delivering DNA into antigen presenting cells”) describes a gene therapy that exploits natural receptor-mediated endocytosis to introduced genes into an antigen-presenting cell. The content of U.S. Pat. Nos. 6,410,517; 6,025,337; and 6,420,176 is hereby incorporated by reference into this specification.
Sensor controlled drug delivery systems are also know to those skilled in the art. U.S. patent applications 2003/0040682 and 2003/0023187 describe systems for sampling and analysis of body fluids by non-invasively withdrawing and evaluating analytes from a biological subject and subsequently administering therapeutic agents. Additional examples of biosensors may be found in U.S. patent application 2003/0032892 wherein the device overcomes the deficiencies of a disease state when inserted into a body passage or implanted into body tissue by providing an apparatus comprised of nanodevices, microdevices and microsensors that determine changes in body conditions. The content of each of the aforementioned applications is hereby incorporated by reference into this specification.
Capsules, also known as nanospheres, nanocapsules, microspheres, or microcapsules, are known to those skilled in the art to deliver antisense oligonucleotides (Advanced Drug Delivery Reviews, v47, p 99–112, 2001). The capsule facilitates intracellular penetration and protects the oligonucleotides until they can exert their inhibitory effects. Birrenbach and Speiser (1976) first developed nanoparticles (J. Pharm. Sci. v65, pp. 1763–1766, 1976). Once biodegradable polymers were available, such capsules could be utilized for drug delivery. At that time, the research on colloidal carriers was mainly focusing on liposomes. Nanoparticles, which are more efficient drug carriers than liposomes, have since been developed (Antimicrobial Agents and Chemotherapy, v35, p 770–772, 1991). It is also known to those skilled in the art that polymers, such as poly-DL-lactic-acid-polyethylene glycol, can be used as a DNA delivery system (J. Controlled Release, v83, pp 147–155, 2002). Delivery of plasmid DNA by nanoparticles made from biodegradable polyphosphoester, poly(2-amino ethyl propylene phosphate) (PPE-EA) improves the DNA bioavailability and sustains extracellular release of the DNA (Gene Therapy, v9, pp 1254–1261, 2002).
It would be advantageous if one could control the release of a therapeutic agent such that the agent is discharged in response to a predetermined signal. One aspect of the instant invention utilizes a cantilever to control the release of such an agent.
As is known to those skilled in the art, a cantilever (also known as a microcantilever) is a microscale bar, typically ranging in size from about 1 to about 200 micrometers, that bends when subjected to a specified condition. A variety of cantilevers have been made which are responsive to numerous conditions such as, for example, specific chemicals, heat, magnetic fields, and the like.
U.S. Pat. No. 6,096,559 to Thundat et al., entitled “Micromechanical calorimetric sensor” discloses a cantilever that is sensitive to thermal changes.
U.S. Pat. No. 6,016,686 to Thundat (“Micromechanical potentiometric sensors”) teaches a cantilever that is responsive to differences in potential charges on either side of the lever. U.S. Pat. No. 5,918,263 to Thundat (“Microcantilever detector for explosives”) describes the use of cantilevers to detect gas molecules that have been absorbed on the surface of the lever. U.S. Pat. No. 6,525,307 to Evens et al., (“Integrated optical Interrogation of micro-structures”) discloses a method for detecting the amount of bending a cantilever has undergone. U.S. Pat. No. 6,311,549 to Thundat et al., (“Micromechanical transient sensor for measuring viscosity and density of a fluid”) teaches a cantilever that may be excited to resonance by vibration, thus providing a method for measuring the viscosity of a fluid. U.S. Pat. No. 5,719,324 to Thundat et al., (“Microcantilever sensor”) is similar in nature. U.S. Pat. No. 6,212,939 to Thundat (“Uncoated microcantilevers as chemical sensors”) describes a cantilever that is responsive to photonic energy. U.S. Pat. No. 5,908,981 to Atalar et al. (“Interdigital deflection sensor for microcantilevers) discloses a similar cantilever assembly. U.S. Pat. No. 5,998,995 to Osiander et al., (“Microelectromechanical (MEMS)-based magnetostrictive magnetometer”) describes a cantilever sensitive to a magnetic field. U.S. Pat. No. 5,807,758 to Lee et al., (“Chemical and biological sensor using an ultra-sensitive force transducer”) teaches a similar cantilever that is indirectly sensitized to a magnetic field. U.S. Pat. No. 5,475,318 to Marcus et al. (“Microprobe”) describes a microcantilever that is thermally sensitive. As the cantilever bends in response to applied heat, the probe is moved into the appropriate position. U.S. Pat. No. 5,445,008 to Wachter et al. (“Microbar sensor”) teaches the use of a microcantilever to absorb chemicals onto the surface of the cantilever. The cantilever is thus caused to oscillate. The mass of the absorbed chemicals causes the oscillation frequency to change, thus providing a method for the detection of the chemicals.
Additional cantilevers have been disclosed which sense specific chemical and/or biological analytes. Reference may be had to U.S. Pat. No. 6,523,392 to Porter et al., (“Microcantilever sensor”), U.S. Pat. No. 6,589,198 to Soltanpour et al. (“Implantable micro-pump assembly”), U.S. Pat. No. 5,643,247 to Fernandez et al., (“Microparticle switching devices for use in implantable reservoirs”), and U.S. Pat. No. 6,289,717 to Thundat et al., (“Micromechanical antibody sensor”). For additional information related to cantilevers, reference may had, for example, to U.S. patent application 2003/0010097 and U.S. Pat. Nos. 5,445,008; 5,475,318; 5,719,324; 5,908,981; 5,918,263; 5,998,995; 6,016,686; 6,096,559; 6,289,717; 6,311,549; 6,523,392; and 6,525,307. The content of U.S. Pat. Nos. 5,445,008; 5,475,318; 5,643,247; 5,719,324; 5,807,758; 5,908,981; 5,918,263; 5,998,995; 6,016,686; 6,096,559; 6,212,939; 6,289,717; 6,311,549; 6,523,392; 6,525,307; 6,589,198 and application 2003/0010097 are hereby incorporated by reference into this specification.
It is an object of this invention to provide a device for increasing the concentration of a therapeutic agent in a given environment by releasing the agent from a capsule in response to the detection of a molecule that is characteristic of a specific disease.